Process for preparing 16 beta-methyl prednisone



United States Patent 3,135,774 PROCESS FQR PREPARING lfi h/EETHYL PREDNISQNE The present invention is concerned with a new process for preparing 16,8-methyl prednisone or l6fl-methyl-pregna-1,4-diene-17a,21-diol-3,11,20-trione and its 21-acetate.

l6 3-methylprednisone is a known steroid, its preparation and its pharmacological activity being described in Journal of the American Chemical Society, 80, 4428 and 4435 (1958); 82, 4012 (1960) and in Annals of New York Academy of Sciences 82, 829 (1959).

The known processes, however, are based on chemical reactions starting from expensive raw materials and operating with low yields. The high cost of the final product thus obtained has till now limited its practical therapeutical use.

Particularly, fl-pregn-l6-en-3u-ol-l1,20-dione-3-acetate has been described as a starting product. It was prepared starting from 5fl-pregnane-3a,17a,2l-triol-11,20-dione-3, Zl-diacetate, a steroid which already contains the 17u-hydroxy and 21-acetoxy groups. These groups however must be first removed to prepare 5B-pregn-16-en-3a-ol-11, 2l-dione-3a-acetate, in which the same groups must be subsequently reintroduced to build up the structure of 165- methylprednisone.

5n pregnane-3a,17d,21-triol-11,20-dione 3,21 diacetate is obtained in turn from bile acids, the side chain of which can be degraded only through several expensive steps and with low yields.

It has now been found that l6-methyl-5a-pregnl6-en- 3153-01-11,20-dione-3B-acetate may advantageously be used as starting compound in the production of l6B-methyl prednisone. It can be easily obtained in good yields from steroids of plant origin as described, for example, in Farmaco 16, 58 (1961). This product has never been used as starting material owing to the difficulty of introducing an hydroxyl group in the 17a-position of an ll-keto-Sapregnane already containing a methyl at position 16. This diificulty is due to the different reactivity of 5aand 518- pregnanes, as described, for example, in Helv. Chim. Acta 42, 2045 (1959) and Chem. and Industry, 1959, 444. Such a transformation has not hitherto been carried out on 5a-pregnanes with satisfactory yields.

The invention resides in introducing an hydroxyl into the Hot-position of the starting compouund l6-methyl-5apregn-l6-en-3fl-ol-11,20-dione-3fi-acetate, by converting this compound into its 16a,17a-epoxide and heating the epoxide with p-toluensulphonic acid in an inert solvent to obtain 16-methy1ene-5a-pregnane-3fi-l'la-diol-l1,20-dione, which on mild reduction with hydrogen surprisingly yields 16B-methyl-5a-pregnane 313,170: diol-11,20-dione which is practically free from the la-isomer. This last mentioned compound can be converted to the desired product 16fi-methylprednisone or its 2l-acetate by a number of successive steps.

The production of 16fi-methyl prednisone or its 2l-ac- 3,135,774 Patented June 2, 1964 'ice ylate may, in accordance with the invention, proceed as follows:

16-methyl 5a pregn-16-en-3B-ol-1L20 dione 3B- acetate (I) is converted into its 16a,17a-epoxide (II) by treatment with hydrogen peroxide in an alcoholic aqueous alkaline solution at room temperature for 15-20 hours; the resulting epoxide is heated with p toluene-sulphonic acid in an inert solvent, for example, benzene, at the boiling temperature of the solvent for 2-3 hours to obtain 16- methylene-Sa-pregnane-3fl,17u-diol-l1,20-dione (HI) This compound (H1) is converted, by mild reduction with hydrogen, using palladium absorbed on an earth alkali metal carbonate as a catalyst, in an inert organic solvent, to 1GB-methyI-Sa-pregnane-BB,17a-diol-11,20-dione (IV), which is practically free from 16a-isomer.

The 16fi-methyl-5a-pregnane-35,17a-di01-l1,20-dione is converted into 16fl-methyl-5a-pregnane-3fl,l7a,2l-triol-l 1, 20-dione-21-acetate (V1) by treatment with bromine in an inert organic solvent at room temperature, evaporation of the solvent to dryness, and refluxing the crude 21- bromo-derivative (V) for 15-18 hours with potassium acetate in aqueous acetone.

By oxidation of compound (VI) with a sulphuric acid solution of chromic acid in acetone 16fl-methyl-5a-pregnane-17a,21-diol-3,l1,20-1rione-21-acetate (VII) is obtained. This latter, through the 2,4-dibromo derivative (VIII) obtained by treatment with bromine in acetic acid, gives the final product by dehydrobromination with a mixture of lithium bromide and lithium carbonate in dimethylformarnide.

The final product, i.e. 16,3-methylprednisone-2l-acetate (]X) can be hydrolysed in known manner to obtain 16,3- methylprednisone.

The reactions described above are schematically illustrated below.

Yields are given to show the industrial importance of the procedure, which enables the production of 16B-methylprednisone, a product of great importance for human therapy, in good amounts and in a high degree of purity.

H2 0 rlNBO H 93-95% yield Br I The following example illustrates thefinvention.

Example To a solution of 29.7 g. of 16-methyl-5a-pregn-l6-en- 35 01-11,20-dione-3fi-acetate in 1000 ml. of methanol, 120 ml. of a 30% hydrogen peroxide Solution and a solution of 13 g. of sodium hydroxide in 120 ml. of water are added, taking care that the temperature does not exceed C. After 1.5 hours at C. and 15 hours at 20- 25 C. under stirring the mixture is diluted with 1000 ml. of a saturated saline solution, then'it is cooled to 0 C. and the precipitate is collected in vacuo, The resulting solid is dissolved in benzene, the solution is dried and diluted with an equal volume .of petroleum ether. The precipitateis collected and dried. Yield 26.2 g. (94.8%) of l6;3-methy1-16a,17a-epoxy-5q-pregnane-3fi-ol-11,20-dione; M.P. 178-183 C. [@1 +88.2 (c. 1, CHCI [oc] +82 (c. 1, dioxane).

A mixture of 25 g. of 16fl-methyl-16a,17a-epoxy-5apregnane-3,B-ol-11,20-dione, 0.6 g. of p-toluenesulphonic acid and 500 ml. of anhydrous benzene is refluxed for 2 hours. .Then it is cooled and the precipitated 16-methylene c pregnane-3/3,17a-diol-ll,20 dione is collected. Yield 24.1 g. (96.5%); M.P. 226-230 C. Although a sample recrystallized from methanol'melts at. 273-278" C., the product is sufficiently pure for the subsequent step.

. [41] 10.2 (c. l, CH OH/CHC1 111).

To a solution, obtained by warming and subsequent cooling of 12 g. of 16-methylene-5a-pregnane-3B,17a-diol-' 11,20-dione in 1000 ml. of anhydrous methanol a suspensionsof'3.6 g. of 5% Pd/CaCO in 200 ml. of anhydrous methanol is added, then it is hydrogenated till no more hydrogen is absorbed.

The catalyst is filtered off and the filtrate is concentrated to about 200 ml. On cooling 16,8-methyl-5a-pregnane-3 8,17u diol-l1,20-dione precipitates and is collected and dried. Yield 11.3 g. (94%); M.P. '227-230 C. [@1 5 +66.7 (c. 0.527, dioxane).

To a suspension of 10 g. of 16,8-methyl-5a pregnane- 3B,].7oz-diO1-1L20-dl0tl6 in 700 m1. of anhydrous chloroform containing 1%ethanol 47.6 g. of a 9.58% bromine solution in anhydrous chloroform are gradually added; the reaction is started by the addition of some millilitres of a hydrogen bromide solution in chloroform. At the end of the addition the solution is made neutral by adding sodium bicarbonate, then it is filtered and concentrated to dryness in vacuo.

The residual crude 2l-bromo derivative is refluxed for 18 hours with 200 ml. of acetone, 16.5 g. of anhydrous potassium acetate and 16.5 g. of Water. The mixture is distilled down to one half its volume, 1000 ml. of water are added and the precipitate is collected. Yield 10.5 g. of l6fl-methyl-5a-pregnane-3a,l704,2l-triol-l1,20- dione-2l-acetate; M.P. 220225 C.

A solution of 16 g. of l6B-methyl-5a-pregnane-3B,17a,

21-triol-11,20-dione-2l-acetate in 1600 ml. acetone is oxidized with 16 ml. of an 8 N chromic acid solution in sulphuric acid (prepared according to J. Chem. Soc. 1953, 2555) under stirring at 5 C.

At the end of the addition the solution is diluted With water to about 1000 m1. and the crystalline precipitate of- 16/3-methyl-5a-pregnane 17a,21 diol-3,11,20-trione'-21- acetate is collected. Yield 15 g.; M.P. 218223 C. (from acetone); [ab +120.4 (c. 0.628, dioxane).

A solution of 12 g. of l6B-methyl-5a-pregnane-170;,21- diol-3,11,20-trione-2l-acetate in ml. of dioxane containing 3 ml. of acetic acid is brominated with a solution of 2.9 g. of bromine in 25 ml. of acetic acid at l2-l5 C. At the end of the addition the mixture is stirred for 90 minutes, poured into 500 m1. ofice water containing 6.2 g. of sodium acetate, stirred again for 30 minutes and filtered. The 2,4-dibronio derivative collected on the filter is sufliciently pure for the subsequent step, M.P. C. (dec.); Br percent found 27.56; calcd. 27.74.

The 2,4-dibromo derivativeis refluxed in 250 ml. of dimethylformarnide under a nitrogen atmosphere with 7 g. of lithium bromide and 7 g. of lithium carbonate for 1 hour. The solution is then concentrated to /3 its volume, cooled and poured into 500 ml. of ice water containing 30 ml. of concentrated hydrochloric acid. The precipitate is dried, dissolved in chloroform andpercolated through 5 times its weight of Florisil. The chloroform solution is evaporated to dryness and the residue taken up with 5 ml. of acetone. The insoluble portion is 16,3- methylprednisone-Zl-acetate (7 g.), M.P. 220-228? C. By recrystallization from ethyl acetate or acetone the M.P. rises to 228-230 C.; [ab +218 (c. 1, CHCI A 238 m (e=15,000)

max.

acetate, which comprises contacting at room temperature l6-methyl-5a-pregn-16-ene-3B-ol-l1,20 dione 3,8-acetate with hydrogen peroxide in the presence of an; alkali metal hydroxide in a mixture of water and a lower aliphatic alcohol, heating the formed 16fi-methyl-16a,l7a-epoxy- 5oz-preg1'lane-3fi-01-1 1,20-dione with p-toluenesulfonic acid in an anhydrous inert organic solvent at the boiling temperature of said solvent, hydrogenating the obtained 16- methylene-5a-pregnane-3,8,17a-diol-1 1,20-dione presence of palladium absorbed on an earth alkalimetal carbonate in an anhydrous inert organic solvent, adding bromine to a solution of the formed IGfi-methyI-Sa-pregnane-3,6,17a-diol-l1,20-dione in an inert organic solvent, evaporating the solvent to dryness and refluxing the residue with potassium acetate in a water-acetone mixture, oxidizing the obtained 1 6 (3-methyl-5a-pregnane-3' 3,17a,21- triol-11,20-dione 2l-acetate with a chromium trioxide solution in sulfuric acid, converting the formed 16,8-methyl- Saregnane-l7u,21-diol-3,11,20-trione ZI-acetate into the 2,4-dibromo derivative by treatment with bromine in acetic acid, and refluxing the 2,4-dibromo derivative with a mixture of lithium bromide and lithium carbonate in dimethylformamide.

in the 2. A process for preparing l6B-methyl-5u-pregnane6p3, 17a-diol-1l,20-dione which comprises contacting at a temperature of 15-30 C. 16-methy1-5a-pregn-l6-ene-3B- ol-11,20-dione 3B-acetate with hydrogen peroxide in the presence of sodium hydroxide in a water-methanol mixture, refluxing the formed IGB-methyl-16a,l7a-epoxy-5upregnane-3fi-ol-1L20-dione with p-toluenesulphonic acid in anhydrous benzene, and hydrogenating the obtained 16-methylene-5a-pregnane-3p,17a-diol-l1,20-dione in the presence of palladium absorbed on calcium carbonate in anhydrous methanol.

References Cited in the file of this patent Pataki et al.: J.A.C.S. 74, pp. 5615-5616 (1952). 

1. A PROCESS FOR PREPARING 16,B-METRHYLPREDNISONE 21ACETATE, WHICH COMPRISES CONTACTING AT ROOM TEMPERATURE 16-METHYL-5A-PREGN-16-ENE-3B-OL-44.20 - DIONE 3B-ACETATE WITH HYDOGEN PEROXIDE IN THE PRESENCE OF AN ALKALI METGAL HYDROXIDE IN A MIXTURE OF WATER AND A LOWER ALIPHATIC ALCOHOL, HEATING THE FORMED 16B-METHYL-16A, 17A-EPOXY5A-PREGANE-3B-OL-11,20-DIONE ITH P-TOLUENESULFONIC ACID IN AN ANHYDROUS INERT ORGANIC SOLVENT AT THE BOILING TEMPERATURE OF SAID SOLVENT, HYDROGENATING THE OBTAINED 16METHYLENE-5A-PREGANE-3B,17A-KIOL-11,20-DIONE IN THE PRESENCE OF PALLADIUM ABSORBED ON AN EARTH ALKALI METAL CARBONATE IN AN ANHYDROUS INERT ORGANIC SOLVENT, ADDING BROMINE TO A SOLUTION OF THE FORMED 16B-METHYL-5A-PREGNANE-3B,17A-DIOL-11,20-DIONE IN AN INERT ORGANIC SOLVENT, EVAPORATING THE SOLVENT TO DRYNESS AND REFLUXING THE RESIDUE WITH POTASSIUM ACTATE IN A WATER-ACETONE MIXTURE, OXIDIZING THE OBTAINED 16B-METHYL-5A-PREGNANE-3B,17A,21TRIOL-11,20-DIONE 21-ACETATE WITH A CHROMIUM TRIOXIDE SOLUTION IN SULFURIC ACID, CONVERTING THE FORMED 16B-METHYL5A-PREGNANE-17A,21-DIOL-3,11,20-TRIONE 21-ACETATE INTO THE 2,4-DIBROMO DERIVATIVE BY TREATMENT WITH BROMINE IN ACETIC ACID, AND REFLUXING THE 2,4-DIBROMO DERIVATIVE WITH A MIXTURE OF LITHIUM BROMIDE AND LITHIUM CARBONATE IN DIMETHYLFORMAMIDE. 